Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 15 de 15
Filter
Add more filters










Publication year range
1.
ACS Chem Biol ; 16(7): 1288-1297, 2021 07 16.
Article in English | MEDLINE | ID: mdl-34232635

ABSTRACT

Inducing the formation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs) represents a potential approach to repairing the loss of myelin observed in multiple sclerosis and other diseases. Recently, we demonstrated that accumulation of specific cholesterol precursors, 8,9-unsaturated sterols, is a dominant mechanism by which dozens of small molecules enhance oligodendrocyte formation. Here, we evaluated a library of 56 sterols and steroids to evaluate whether other classes of bioactive sterol derivatives may also influence mouse oligodendrocyte precursor cell (OPC) differentiation or survival. From this library, we identified U-73343 as a potent enhancer of oligodendrocyte formation that induces 8,9-unsaturated sterol accumulation by inhibition of the cholesterol biosynthesis enzyme sterol 14-reductase. In contrast, we found that mouse OPCs are remarkably vulnerable to treatment with the glycosterol OSW-1, an oxysterol-binding protein (OSBP) modulator that induces Golgi stress and OPC death in the low picomolar range. A subsequent small-molecule suppressor screen identified mTOR signaling as a key effector pathway mediating OSW-1's cytotoxic effects in mouse OPCs. Finally, evaluation of a panel of ER and Golgi stress-inducing small molecules revealed that mouse OPCs are highly sensitive to these perturbations, more so than closely related neural progenitor cells. Together, these studies highlight the wide-ranging influence of sterols and steroids on OPC cell fate, with 8,9-unsaturated sterols positively enhancing differentiation to oligodendrocytes and OSW-1 able to induce lethal Golgi stress with remarkable potency.


Subject(s)
Cell Differentiation/drug effects , Oligodendrocyte Precursor Cells/drug effects , Sterols/pharmacology , Animals , Cell Survival/drug effects , Cholestenones/pharmacology , Cholestenones/toxicity , Drug Evaluation, Preclinical , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum Stress/drug effects , Estrenes/pharmacology , Golgi Apparatus/drug effects , HeLa Cells , Humans , Mice , Oligodendrocyte Precursor Cells/metabolism , Oligodendroglia/metabolism , Pyrrolidinones/pharmacology , Saponins/pharmacology , Saponins/toxicity , Small Molecule Libraries/pharmacology , Small Molecule Libraries/toxicity , Sterols/toxicity
2.
Steroids ; 140: 11-23, 2018 12.
Article in English | MEDLINE | ID: mdl-30149072

ABSTRACT

Identification and characterization of marine natural products with antimicrobial, antioxidant activity with minimal toxicity has received much interest over the past few years. Among, Acropora formosa is one of the unexplored marine organism for the screening of natural products in marine resources. In this study, a novel steroid 2-ethoxycarbonyl-2-ß-hydroxy-A-nor-cholest-5-ene-4one (ECHC) was isolated from butanol extracts of A. formosa using vacuum liquid chromatography and sequentially purified by column chromatography. The chemical structure of the compound was elucidated based on spectroscopic analysis including GC-MS, 1H NMR and 13C NMR and identified as ECHC. Moreover, in vitro antioxidant activity showed that ECHC was highly scavenged the oxidative stress generative molecules. The in vitro cytotoxic activity of ECHC showed excellent activity against human breast cancer cells. Further, in vivo acute toxicity of ECHC on zebrafish Danio rerio was showed no toxicity as well as no morphological damage was observed after 21 days exposure. Histological analysis revealed that there is no apparent difference was observed between ECHC exposure and control group of D. rerio. Together, these results confirmed that ECHC has in vitro antioxidant and anticancer activity and could be developed as a potential drug against most contagious disease like cancer.


Subject(s)
Anthozoa/chemistry , Cholestenones/isolation & purification , Cholestenones/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Antioxidants/chemistry , Antioxidants/isolation & purification , Antioxidants/pharmacology , Antioxidants/toxicity , Cell Line, Tumor , Cholestenones/chemistry , Cholestenones/toxicity , Humans , Zebrafish
4.
Steroids ; 78(4): 396-400, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23352845

ABSTRACT

Five new steroids, (12ß, 22R)-12-acetoxy-22-hydroxy-cholesta-1,4-dien-3-one (1), (12ß, 22R)-12-hydroxy-22-acetoxy-cholesta-1, 4-dien-3-one (2), (12ß, 22R)-12, 22-diacetoxy-cholesta-1, 4-dien-3-one (3), (22R)-18, 22-diacetoxy-cholesta-1, 4-dien-3-one (4), (20R, 22R)-20-hydroxy-22-acetoxy-cholesta-1, 4-dien-3-one (5), and one known steroid astrogorgol N (6), were isolated from soft coral Nephthea sp. Their structures were established by spectroscopic analysis (1D, 2D NMR, HRMS) and comparisons of their spectral data with those of related steroids. The absolute configuration at C-22 of 1 was determined to be R by Mosher's analysis. All isolated compounds exhibited cytotoxic activity against HeLa cells with IC50 values ranged from 7.51±0.22 to 18.72±0.78µg/mL.


Subject(s)
Anthozoa/chemistry , Cholestenones/pharmacology , Cholestenones/toxicity , Animals , Cell Death/drug effects , Cell Proliferation/drug effects , Cholestenones/chemistry , Cholestenones/isolation & purification , Dose-Response Relationship, Drug , HeLa Cells , Humans , Molecular Conformation , Structure-Activity Relationship
6.
Bioorg Med Chem ; 16(3): 1460-73, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-17983753

ABSTRACT

Starting from (22E)-3alpha,5alpha-cyclo-6beta-methoxystigmast-22-ene eighteen derivatives of (22S,23S)-22,23-oxidostigmastane, (22R,23R)-22,23-oxidostigmastane, and (22R,23R)-22,23-dihydroxystigmastane were synthesized and screened for cytotoxicity in human hepatoma Hep G2 cells and human breast carcinoma MCF-7 cells using MTT assay. Four compounds of this series exhibited high cytotoxicity in both cells; three compounds were selectively toxic in MCF-7 cells, one compound was toxic in Hep G2 cells, rather than in MCF-7 cells; four compounds at low concentrations increased MTT test values over the control.


Subject(s)
Cholestenones/chemical synthesis , Cholestenones/toxicity , Oxygen/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Cholestenones/chemistry , Humans , Models, Molecular , Molecular Structure , Protons , Stereoisomerism , Structure-Activity Relationship
7.
Steroids ; 73(3): 252-6, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18054370

ABSTRACT

Using beta-sitosterol as a starting material, (6E)-hydroximino-24-ethylcholest-4-en-3-one (1), a natural steroidal oxime from Cinachyrella alloclada and C. apion, was synthesized in four steps with a high overall yield. First, beta-sitosterol (5a) is transformed into the corresponding 24-ethylcholest-4-en-3,6-dione (6a) via oxidation with pyridinium chlorochromate (PCC). Selective reduction of 6a by NaBH(4) in the presence of CoCl(2) gives 24-ethylcholest- 4-en-3beta-ol-6-one (7a). The reaction of 7a with hydroxylamine hydrochloride offers the oxime 8a and the oxidation of 8a by Jones reagent gives the target steroid 1. (6E)-Hydroximinocholest-4-en-3-one (2) and (6E)-hydroximino-24-ethylcholest-4,22-dien-3-one (4) were synthesized by a similar method. The cytotoxicity of the synthesized compounds against sk-Hep-1 (human liver carcinoma cell line), H-292 (human lung carcinoma cell line), PC-3 (human prostate carcinoma cell line) and Hey-1B (human ovarian carcinoma cell line) cells were investigated. The presence of a cholesterol-type side chain appears to be necessary for the biological activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cholestadienes/chemical synthesis , Cholestenones/chemical synthesis , Oximes/chemical synthesis , Porifera/chemistry , Steroids/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cholestadienes/toxicity , Cholestenones/toxicity , Humans , Oximes/chemistry , Porifera/classification , Steroids/chemistry
8.
Bioorg Med Chem Lett ; 17(20): 5506-9, 2007 Oct 15.
Article in English | MEDLINE | ID: mdl-17826089

ABSTRACT

The A,B-ring-truncated OSW saponin analogs (1, 18a, and 18b) were synthesized. These greatly simplified trans-hydrindane disaccharides retained considerable inhibitory activity against the growth of HeLa and Jurkat T cells (IC(50)=0.8-21.1 microM).


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Cholestenones/chemistry , Cholestenones/toxicity , Saponins/chemistry , Saponins/toxicity , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cholestenones/chemical synthesis , Humans , Inhibitory Concentration 50 , Molecular Structure , Saponins/chemical synthesis , Structure-Activity Relationship
9.
J Med Chem ; 47(21): 5210-23, 2004 Oct 07.
Article in English | MEDLINE | ID: mdl-15456264

ABSTRACT

Cationic lipid-mediated gene transfection involves uptake of the lipid/DNA complexes via endocytosis, a cellular pathway characterized by a significant drop in pH. Thus, in the present study, we aimed to explore the impact on transfection efficiency of the inclusion of an acid-sensitive acylhydrazone function in the cationic lipid structure. We synthesized and evaluated the transfection properties of a series of four cationic steroid derivatives characterized by an acylhydrazone linkage connecting a guanidinium-based headgroup to a saturated cholestanone or an unsaturated cholest-4-enone hydrophobic domain. Acid-catalyzed hydrolysis was confirmed for all lipids, its rate being highest for those with a cholestanone moiety. The compound bis-guanidinium bis(2-aminoethyl)amine hydrazone (BGBH)-cholest-4-enone was found to mediate efficient gene transfection into various mammalian cell lines in vitro and into the mouse airways in vivo. In vitro transfection studies with BGBH-cholest-4-enone formulations also showed that incorporation of a degradable acylhydrazone bond led to low cytotoxicity and impacted the intracellular trafficking of the lipoplexes. Thus, our work allowed us to identify a cationic lipid structure with an acid-cleavable acylhydrazone linker capable of mediating efficient gene transfection in vitro and in vivo and it thereby provides a basis for further development of related acid-sensitive gene delivery systems.


Subject(s)
Cholestenones/chemical synthesis , Hydrazones/chemistry , Hydrazones/chemical synthesis , Lipids/chemical synthesis , Lung/metabolism , Animals , Cations/chemistry , Cell Line , Cholestenones/chemistry , Cholestenones/toxicity , DNA/administration & dosage , Female , Genes, Reporter , Humans , Hydrazones/toxicity , Hydrolysis , Instillation, Drug , Lipids/chemistry , Lipids/toxicity , Liposomes , Luciferases/biosynthesis , Luciferases/genetics , Mice , Mice, Inbred BALB C , Structure-Activity Relationship , Transfection
10.
Arch Pharm Res ; 25(5): 608-12, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12433190

ABSTRACT

The twelve-protostane analogues were synthesized from alisol B 23-acetate and assessed for their in vitro antitumor activity against six different human and murine tumor cell lines. Of the compounds synthesized, 23S-acetoxy-24R(25)-epoxy-11beta,23S-dihydroxyprotost-13(17)-en-3-hydroxyimine (12) exhibited significant cytotoxic activities against A549, SK-OV3, B16-F10, and HT1080 tumor cells with ED50 values of 10.0, 8.7, 5.2, and 3.1 microg/ml, respectively. Furthermore, 23S-acetoxy-13(17),24R(25)-diepoxy-11beta-hydroxyprotost-3-one (5), 13(17),24R(25)-diepoxy-11beta,23S-dihydroxyprotostan-3-one (6), 24R,25-epoxy-11beta,23S-dihydroxyprotost-13(17)-en-3-one (7), and 11beta,23S,24R,25-tetrahydroxyprotost-13(17)-en-3-one (9) showed moderate cytotoxic activities against B16-F10 and HT1080 tumor cells. These results mean that a hydroxyimino group at C-3 position in the protostane-type terpene enhances cytotoxic activity.


Subject(s)
Cholestenones/chemistry , Cholestenones/toxicity , Acetates/chemistry , Acetates/toxicity , Animals , Drug Screening Assays, Antitumor/methods , Humans
11.
J Nat Prod ; 55(3): 321-5, 1992 Mar.
Article in English | MEDLINE | ID: mdl-1350615

ABSTRACT

Four new polyoxygenated sterols 2-5 were isolated from the marine black coral Antipathes subpinnata. The structures of these compounds, including stereochemical details, were deduced by ms, 1H- and 13C-nmr, 1H-1H COSY, and nOe difference spectroscopy. Compounds 2-5 are lethal to brine shrimp (Artemia salina).


Subject(s)
Cholestadienols/isolation & purification , Cholestenones/isolation & purification , Cnidaria/chemistry , Decapoda/physiology , Sterols/isolation & purification , Animals , Cholestadienols/toxicity , Cholestenones/toxicity , Lethal Dose 50 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Sterols/toxicity
12.
Toxicol Pathol ; 17(3): 506-15, 1989.
Article in English | MEDLINE | ID: mdl-2814226

ABSTRACT

The morphological effects of short-term (9 days) dietary administration (0.1% in a laboratory chow diet) of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a novel regulator of cholesterol metabolism with significant hypocholesterolemic activity, has been studied in young male rats. Control animals included rats fed the basal diet ad libitum and a series of rats pair-fed to the individual experimental animals. At the time of necropsy, the morphological changes in rats which have been observed in rats following treatment with other absorbable hypolipidemic agents (myeloid bodies with triparanol, increased peroxisomes with clofibrate, and proliferation of smooth endoplasmic reticulum with compactin and mevinolin) were not apparent on ultrastructural examination of livers of rats treated with the 15-ketosterol. Two changes were observed in the rats fed the 15-ketosterol: a decrease in adipose tissue and enlargement of the small intestine. Diminished fat was also noted in the pair-fed controls and was presumably due to decreased food consumption. The intestines of rats fed the 15-ketosterol were morphometrically most enlarged in the jejunal region. Morphologically, this increase was distinguished by increased depth of crypts of Lieberkuhn and pseudostratification of epithelium at the base of the villi. These changes were qualitatively and quantitatively similar to the adaptive changes reported in the rat after resection of small bowel or following intestinal bypass (segment of bowel remaining in continuity). The morphological changes induced in the rat by administration of the 15-ketosterol were not observed in 4 baboons which received the compound orally at doses of 50, 75, or 100 mg per kilogram of body weight for up to 3 months.


Subject(s)
Anticholesteremic Agents/toxicity , Cholestenes/toxicity , Cholestenones/toxicity , Animals , Body Weight/drug effects , Cholesterol/blood , Diet , Eating/drug effects , Intestinal Mucosa/pathology , Intestine, Small/pathology , Male , Rats , Rats, Inbred Strains , Time Factors
13.
Mutagenesis ; 2(6): 441-4, 1987 Nov.
Article in English | MEDLINE | ID: mdl-3328036

ABSTRACT

Two components of human feces are known to induce nuclear anomalies in mice when applied intrarectally, but to be nonmutagenic in Salmonella. We have tested these two compounds for their ability to induce sister chromatid exchanges in the colonic epithelium of mice, the same tissue in which they induce nuclear anomalies when administered by the same route. One, 4-cholesten-3-one, induced sister chromatid exchanges whereas the other, 5-alpha-cholestan-3-one did not, even at the maximum feasible dose. The results suggest that 4-cholesten-3-one is more likely to be a significant factor in human colon cancer than the 5-alpha analog.


Subject(s)
Cholestanes/toxicity , Cholestenes/toxicity , Cholestenones/toxicity , Colon/drug effects , Sister Chromatid Exchange/drug effects , Animals , Colon/pathology , Epithelial Cells , Epithelium/drug effects , Feces/analysis , Humans , Male , Mice , Mice, Inbred C57BL , Mutagenicity Tests
14.
Am J Clin Nutr ; 32(5): 1033-42, 1979 May.
Article in English | MEDLINE | ID: mdl-34998

ABSTRACT

Aortic smooth muscle cell death is an important initial lesion of atherosclerosis. A number of autooxidation products of cholesterol which has been recognized recently has the capability of inducing rabbits' aortic smooth cell death in vitro. Twelve oxidation derivatives of cholesterol, available commercially, were dissolved in small amounts of ethanol, then added to the culture medium at levels not exceeding 0.8%. The medium contained 10% fetal calf's serum which served as an in situ vehicle for the sterols. The degrees of cytotoxicity were graded and measured as percentage of dying and dead cells in the cultures within 24 hr. 25-Hydroxycholesterol and cholesthan-3 beta, 5 alpha, 6 beta-triol, were the most toxic compounds among the sterols tested. When these oxidation derivatives of cholesterol were added to these cultured cells, they significantly depressed activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a regulatory enzyme of cholesterol biosynthesis (up to 83% inhibition by 25 hydroxycholesterol at a 3 microgram/ml concentration in culture medium) but the sequence of degree of inhibition was not exactly correlated with that of cytotoxicity. Various mechanisms are speculated. Purified cholesterol showed no cytotoxic effect and minimal inhibition of cholesterol biosynthesis.


Subject(s)
Aorta/metabolism , Cholesterol/biosynthesis , Cytotoxins , Animals , Aorta/cytology , Aorta/drug effects , Cells, Cultured , Cholestanols/toxicity , Cholestanones/toxicity , Cholestenones/toxicity , Cholesterol/toxicity , Hydroxycholesterols/toxicity , Hydroxymethylglutaryl-CoA Synthase/metabolism , Ketosteroids/toxicity , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Oxidation-Reduction , Rabbits
15.
Appl Environ Microbiol ; 34(5): 576-81, 1977 Nov.
Article in English | MEDLINE | ID: mdl-931377

ABSTRACT

Epichloë typhina, a clavicipitaceous systemic phytopathogen, was isolated from two varieties and three hybrids of tall fescue (Festuca arundinaceae). The morphology of the fescue isolates was compared with E. typhina isolated from bent grass (Agrostis perennans). In all isolates, conidia were identical and were typical of E. typhina. In fescue grasses the endophyte failed to produce stromata, but on bent grass the fungus seasonally produced stromata, typical of the genus. Cattle grazing the fescue grasses showed signs of the fescue toxicity syndrome, the E. typhina was found in frequencies of 100%; in grasses from pastures in which cattle showed no signs of the syndrome, frequencies were 0 to 50%. Nutritional factors in vitro were more complex for the isolates from fescue than for the isolate from bent grass. These studies suggested that E. typhina includes biotypes that might be involved in the toxicity syndrome. The fescue biotypes grew poorly on media, and yields were inadequate for toxicity studies. However, the bent grass isolate grew well on three media, and extracts from two of these were toxic to chicken embryos. All isolates produced in vitro the nontoxic fungal steroid tetraenone [ergosta-4,6,8(14),22-tetraen-3-one], which has been isolated from toxic fescue grasses.


Subject(s)
Ascomycota/growth & development , Cattle Diseases/microbiology , Plant Poisoning/veterinary , Poaceae/microbiology , Animals , Ascomycota/metabolism , Cattle , Chick Embryo , Cholestenones/biosynthesis , Cholestenones/toxicity , Plant Poisoning/microbiology , Syndrome/veterinary
SELECTION OF CITATIONS
SEARCH DETAIL
...